Journal of Medical Genetics最新文献

{"title":"<i>AUTS2</i> disruption underlies radioulnar synostosis and skeletal dysmorphogenesis: evidence from four unrelated cases.","authors":"Cheng Liu, Fang Shen, Mei Deng, Chuanchun Yang, Luyang Zhao, Guanghui Zhu, Hua Wang, Zhuo Li, Yongjia Yang","doi":"10.1136/jmg-2025-110886","DOIUrl":"10.1136/jmg-2025-110886","url":null,"abstract":"<p><strong>Background: </strong>While <i>AUTS2</i> is recognised as a pivotal neurodevelopmental gene, its role in skeletal morphogenesis has remained unexplored. We investigated the contribution of <i>AUTS2</i> to radioulnar synostosis (RUS) and associated skeletal dysplasias through integrated molecular and phenotypic analyses of unrelated probands.</p><p><strong>Methods: </strong>Comprehensive genetic profiling was performed on patients with RUS, including G-banding karyotyping, translocation breakpoint mapping via low-coverage whole-genome sequencing with PCR/Sanger validation, CNV detection using SNP array (Infinium OmniZhongHua-8) and qPCR, and exome sequencing followed by orthogonal Sanger confirmation.</p><p><strong>Results: </strong>Four novel pathogenic <i>AUTS2</i> variants were identified from four unrelated patients: a balanced translocation [46,XY,t(7;21)(q11.22;q21.1)] disrupting intron 5 (hg19:chr7:71,845,797); a heterozygous 2.99 Mb deletion (hg19:7q11.22[67,488,531-70,480,818]) spanning AUTS2 and flanking loci; and two de novo frameshift insertions (c.47_48insG; c.864_865insGGACTGTTGCAAAGAGCCA). All variants impaired the full-length <i>AUTS2</i> transcript. Affected individuals exhibited RUS accompanied by additional skeletal anomalies (micrognathia, short stature, dysplasia of hip joint, tight heel cords) and other AUTS2 syndrome features. Notably, phenotypic overlap with Tsukahara syndrome (OMIM 603438) was observed, suggesting potential diagnostic continuity between these entities.</p><p><strong>Conclusion: </strong>This study establishes <i>AUTS2</i> as a critical regulator of skeletal development, with molecular disruptions directly linked to RUS pathogenesis and broader skeletal dysmorphogenesis.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic loss-of-function variants in <i>C19orf44</i> lead to retinal degeneration.","authors":"Hafiz Muhammad Jafar Hussain, Wang Meng, Yumei Li, Sabika Firasat, Mark E Pennesi, Michael B Gorin, Bin Guan, Rebecca Lynn Clark, Emma Fale-Olsen, Ranya Al Rawi, Aime Agather, Laryssa A Huryn, Paul Yang, Anna Matynia, Rui Chen","doi":"10.1136/jmg-2025-110681","DOIUrl":"https://doi.org/10.1136/jmg-2025-110681","url":null,"abstract":"<p><strong>Background: </strong>Inherited retinal diseases (IRDs) are a group of disorders often resulting in progressive vision loss, ultimately leading to blindness. A significant portion of their genetic causes remain unresolved, partly due to undiscovered disease-associated genes or variants. This study aimed to identify novel genetic links to IRDs.</p><p><strong>Methods: </strong>All patients underwent comprehensive ophthalmological evaluation, including retinal imaging (fundus autofluorescence and macular optical coherence tomography) and electroretinogram testing. Whole exome sequencing and whole genome sequencing were performed on patients with clinically unsolved IRD, and data were analysed using an in-house pipeline to identify causal variants. Subsequently, Sanger sequencing was performed to confirm identified variants.</p><p><strong>Results: </strong>Three unrelated patients from Europe, Middle East and East Asia were identified with unique late-onset retinal degeneration (Stargardt-like phenotype) associated with biallelic loss-of-function (LoF) variants in <i>C19orf44</i> (HGNC: 26141), a gene of unknown function. The homozygous variant NM_032207.2:c.549_550del;p.Ser185Profs*2 was identified in two unrelated patients (European and Middle Eastern). Moreover, an East Asian patient had likely compound heterozygous LoF variants (NM_032207.2:c.1168C>T;p.Gln390*/c.976_977del;p.Leu326Lysfs*15).</p><p><strong>Conclusions: </strong>Our findings establish <i>C19orf44</i> as a novel disease-causing gene for IRD with Stargardt-like phenotype, expanding the genetic landscape of retinal degeneration.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Congenital heart disease in 22q11.2 deletion syndrome: a meta-analysis and systematic review of the literature.","authors":"Carina Sauter, Michael Hofbeck, Paula Franz, Laura Kettenstock, Klara Steger, Matthias Linhardt, Andrea Reiter, Stefan Störk, Marcel Romanos, Franziska Radtke","doi":"10.1136/jmg-2025-110624","DOIUrl":"https://doi.org/10.1136/jmg-2025-110624","url":null,"abstract":"<p><p>The 22q11.2 deletion syndrome (22q11.2DS) results from a heterozygous deletion at chromosomal locus 22q11.2 and is associated with multisystem symptoms, including cardiovascular, psychiatric and palatal manifestations. Although congenital cardiovascular aberrations are frequent in patients with 22q11.DS, exact prevalence figures remain unclear. Literature was searched in August 2022 and updated in May 2024 using the databases PubMed, Web of Science and Cochrane library to retrieve studies in English and German focusing only on studies involving 22q11.2DS. Prevalence data for cardiovascular aberrations were arcsine transformed and summarised by random-effects models using Meta-XL. Evidence quality was assessed via the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. The systematic searches identified 4338 studies, of which 7 were included for the meta-analysis of prevalence using random-effects models and sensitivity analyses. The pooled prevalence for heart defects (mean; 95% CI) was found to be elevated for tetralogy of Fallot (20%; 0.17 to 0.23), ventricular septal defect (14%; 0.12 to 0.16), pulmonary atresia with ventricular septal defect (9%; 0.06; 0.12), interrupted aortic arch (10%; 0.06 to 0.15), truncus arteriosus communis (9%; 0.07 to 0.12) and atrial septal defect (3%; 0.01 to 0.04). The risk of bias of the included studies was low to moderate. This study, to our knowledge, represents the first systematic review and meta-analysis of prevalences for congenital cardiovascular aberrations in individuals with 22q11.2DS. The high frequencies observed underline the need for cardiovascular screening in patients with 22q11.2DS and genetic screening for 22q11.2DS in congenital heart disease.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accurate detection of D4Z4 repeats, methylation and allele haplotype in facioscapulohumeral muscular dystrophy 1 using nanopore long-read adaptive sampling sequencing: a pilot study.","authors":"Mingtao Huang, Qinxin Zhang, Sihui Wu, Yixuan Liang, Yan Wang, Zhengfeng Xu, Ping Hu","doi":"10.1136/jmg-2025-110827","DOIUrl":"https://doi.org/10.1136/jmg-2025-110827","url":null,"abstract":"<p><strong>Background: </strong>Facioscapulohumeral muscular dystrophy 1 (FSHD1) is one of the most common autosomal dominant neuromuscular diseases. Genetic diagnosis of FSHD1 remains a challenge because of the long length and repetitive nature of D4Z4 repeats. Long-read sequencing is an effective method for detecting FSHD1, but sequencing depth remains a limitation.</p><p><strong>Methods: </strong>We developed a long-read library adaptive sampling (LRL-AS) method based on Oxford Nanopore Technologies (ONT) sequencing to comprehensively detect FSHD1. Two patients were sequenced by adaptive sampling, followed by analyses of D4Z4 repeat units (RUs), methylation and haplotype.</p><p><strong>Results: </strong>Compared with whole-genome sequencing, our LRL-AS method shows significant improvements in both sequencing depth and read length. LRL-AS can identify D4Z4 RUs contraction with accuracy comparable to optical genome mapping in both 4q35 and 10q26 regions. We also calculated methylation levels in the double homeobox 4 (<i>DUX4</i>) gene region. With the benefit of higher sequencing depth, allele-specific methylation can be calculated with greater precision. We also observed that, at different sequencing depths, ONT sequencing data consistently provide stable calculations of methylation levels. More importantly, we demonstrated that data from adaptive sampling can be effectively used to construct the haplotype of the pathogenic allele using single-nucleotide polymorphisms.</p><p><strong>Conclusion: </strong>Our LRL-AS method is a comprehensive approach for FSHD1 detection, improving the accuracy of D4Z4 RUs and methylation detection while enabling allele-specific haplotype construction. It holds promising potential for clinical application.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"'Knowing and Treating Kosaki/Penttinen syndrome' international collaborative consortium: recommendations for follow-up, natural history and a real-life observational study about safety and efficacy profile of tyrosine kinase inhibitors.","authors":"Yordi-Michaël Bouhatous, Cecilie Bredrup, Agnes Maurer, Liubinka Mirakovska, Alison Foster, Kenjiro Kosaki, Céline Jost, Jean-Baptiste Demoulin, Maxime Luu, Pierre Vabres, Jean-Emmanuel Kurtz, Elise Schaefer, Anne Guimier, Valerie Cormier-Daire, Derek Lim, Sarah Thompson, Lorin Olson, Hae Ryong Kwon, Cristina Aguirre-Rodriguez, Unai Hernandez-Dorronsoro, Itziar Martinez-Soroa, Helena Iznardo, José-Manuel Mascaró, Eulalia Baselga, Silvia Kalantari, Alessandro Mussa, Andrea Gazzin, Diana Carli, Ingrid Svinvik, Hatice Mutlu-Albayrak, Sarah Bluefeather, Yuri Zarate, Toshiki Takenouchi, Thirona Naicker, Antoinette Chateau, Ashmika Gokhul, Anele Dube-Pule, Muzhirah Haniffa, Winnie Ong Peitee, Ann Nordgren, Maud Carpentier, Christine Binquet, Anne-Sophie Briffaut, Laurence Bal, Dinel Pond, Cecilie F Rustad, Marc Bardou, Laurence Faivre","doi":"10.1136/jmg-2024-110600","DOIUrl":"https://doi.org/10.1136/jmg-2024-110600","url":null,"abstract":"<p><strong>Background: </strong>5 years have passed since the formation of the multidisciplinary consortium 'Knowing & Treating Kosaki and Penttinen Syndromes', two ultra-rare degenerative multisystem syndromes caused by heterozygous activating variants in <i>PDGFRB</i>. Neurological, orthopaedic and vascular deterioration can occur. Case reports of patients treated with tyrosine kinase inhibitors (TKIs) suggest that these drugs may be a therapeutic option in the future. The bi-annual remote meetings provide an opportunity to share knowledge on these syndromes.</p><p><strong>Material and methods: </strong>The consortium has validated the communication process, standardised follow-up guidelines, established a database to improve the natural history of these syndromes and evaluated the real-world safety and efficacy profile of TKIs by comparing treated and untreated patients. The regulatory framework is in place.</p><p><strong>Results: </strong>As of November 2024, 18 teams in 13 countries have joined the consortium. More than 25 patients have been identified worldwide, either published or unpublished; 7 of them were treated with a TKI. The guidelines include retrospective and prospective sections for each organ affected by the disease and are based on literature and expert opinion. They also include recommendations to standardise the assessment of the efficacy and safety of treatments prescribed under compassionate use.</p><p><strong>Conclusion: </strong>The consortium welcomes new teams on an ongoing basis. Recommendations are especially useful in such ultra-rare degenerative diseases. The real-life observational study seems to be an appropriate model to improve knowledge, including the assessment of treatment efficacy when the prevalence of the disease does not allow the setting up of clinical trials.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144707736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contemporary practice and resource availability for genetic testing in paediatric hypertrophic cardiomyopathy.","authors":"Christoph Sandmann, Sabine Klaassen, Juan Pablo Kaski, Gabrielle Norrish","doi":"10.1136/jmg-2025-110696","DOIUrl":"10.1136/jmg-2025-110696","url":null,"abstract":"","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"528-530"},"PeriodicalIF":3.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and genetic characteristics of <i>PLA2G6</i>-related parkinsonism in Southwest China and a comprehensive literature review.","authors":"Yangfan Cheng, Yang Zhang, Yi Xiao, Shichan Wang, Sihui Chen, Xiaoting Zheng, Tianmi Yang, Qirui Jiang, Jingxuan Huang, Junyu Lin, Ruwei Ou, Chunyu Li, Qianqian Wei, Xueping Chen, Huifang Shang","doi":"10.1136/jmg-2024-110479","DOIUrl":"10.1136/jmg-2024-110479","url":null,"abstract":"<p><strong>Background: </strong>Biallelic <i>PLA2G6</i> mutations are associated with early onset autosomal recessive parkinsonism, exhibiting a broad spectrum of clinical heterogeneity.</p><p><strong>Objective: </strong>To comprehensively characterise the clinical, imaging and genetic features of <i>PLA2G6</i>-related parkinsonism.</p><p><strong>Methods: </strong>We report 14 new cases of <i>PLA2G6</i>-related parkinsonism in Southwest China and conduct a systematic literature review.</p><p><strong>Results: </strong>Among the 14 patients in our cohort, 16 <i>PLA2G6</i> variants were identified, including seven novel and nine previously reported variants. The mean age at symptom onset was 26.50±6.57 years. The most common initial presentation was parkinsonism (9/14, 64.3%), followed by gait disturbance (6/14, 42.9%) and psychiatric symptoms (1/14, 7.1%). A literature review identified 118 patients with <i>PLA2G6</i>-related parkinsonism, with a mean age at onset of 24.53±8.84 years. The most common initial clinical features included parkinsonism (61/117, 52.1%), cerebellar signs (46/85, 54.1%), cognitive impairment (65/92, 70.7%) and psychiatric symptoms (80/93, 86.0%). Subgroup analysis showed that the mean age at symptom onset was older in Chinese patients (26.65±7.08 years) compared with those of European ancestry (20.83±9.79 years) (p=0.016). Additionally, patients of European ancestry showed delayed parkinsonism 5.35±8.14 years after onset. Iron deposition was reported more frequently in patients of European ancestry (10/16, 62.5%) than that in Chinese patients (6/37, 16.2%) (p=0.0002).</p><p><strong>Conclusion: </strong>Our study provides new insights on the diverse clinical spectrum of <i>PLA2G6</i>-related parkinsonism, encompassing parkinsonian features, psychiatric symptoms, cognitive impairment and early levodopa-induced motor complications.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"508-515"},"PeriodicalIF":3.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Incidence of positive genetic testing among patients referred for cardiac positron emission tomography.","authors":"Kathleen Trinh, Annika Dries, Kristin Boulier, Jessica Wang","doi":"10.1136/jmg-2025-110626","DOIUrl":"10.1136/jmg-2025-110626","url":null,"abstract":"<p><strong>Background: </strong>Positron emission tomography-CT (PET-CT) is widely used to diagnose cardiac sarcoidosis (CS). Emerging evidence suggests genetic arrhythmogenic cardiomyopathies (ACMs) may similarly present with episodes of myocardial inflammation resembling CS. We hypothesise a high rate of ACM diagnosis and associated pathogenic variants in patients with positive cardiac PET-CT scans referred for genetic testing. This study also seeks to delineate the role of PET-CT and anti-inflammatory therapy in ACM.</p><p><strong>Methods: </strong>Patients at the UCLA Cardiovascular Genetics Clinic who underwent a cardiomyopathy gene panel were included. Genotypes were classified as genotype-positive (pathogenic or likely pathogenic variants), uncertain (variant of uncertain significance) or negative. Genes were grouped into ACM or non-ACM. PET-CT positivity was defined by cardiac fludeoxyglucose uptake without extracardiac involvement.</p><p><strong>Results: </strong>Among 48 patients receiving PET-CT scans, 48% (23/48) were genotype-positive. Of 268 patients with pathogenic/likely pathogenic variants, 23 (8.6%) underwent PET-CT (11 ACM, 12 non-ACM). PET-CT positivity was observed in 27% (3/11) of ACM and 8% (1/12) of non-ACM cases. Two PET-CT-positive patients (<i>FLNC</i>, <i>MYH7</i>) received steroids with variable outcomes.</p><p><strong>Conclusion: </strong>Receiving a PET-CT scan yielded a high genetic diagnostic yield (48%) in our clinic. Randomised controlled trials of immunosuppressive responsiveness and novel therapeutics are needed to address treatment gaps for ACM.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"523-527"},"PeriodicalIF":3.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using long-read sequencing to detect and subtype a case with Temple syndrome.","authors":"Sarah Dada, Vahid Akbari, Duha Hejla, Yaoqing Shen, Katherine Dixon, Sanaa Choufani, Rosanna A Weksberg, Cornelius F Boerkoel, Laura Stewart, Kamilla Schlade-Bartusiak, Emma Strong, Danya Fox, Daniel Gamu, William T Gibson, Steven J M Jones","doi":"10.1136/jmg-2024-110262","DOIUrl":"10.1136/jmg-2024-110262","url":null,"abstract":"<p><p>Temple syndrome is an imprinting disorder resulting from abnormal genomic or epigenomic aberrations of chromosome 14 including maternal uniparental disomy (matUPD), paternal deletion of 14q32, or aberrant methylation of the imprinting control regions at 14q32. Understanding the underlying molecular mechanism is essential to understanding the recurrence risk and physical effects. Currently, diagnosis requires the detection of aberrant methylation and copy number loss via methylation-sensitive assays such as methylation-specific multiplex ligation-dependent probe amplification, and short tandem repeat analysis to detect matUPD and the presence of epimutation. Therefore, a one-step approach that can detect aberrant methylation and underlying genetic mechanisms would be of high clinical value. Here we use nanopore sequencing to delineate the molecular diagnosis of a case with Temple syndrome. We demonstrate the application of nanopore sequencing to detect aberrant methylation and underlying genetic mechanisms simultaneously in this case, thus providing a proof of concept for a one-step approach for molecular diagnosis of this disorder.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"502-507"},"PeriodicalIF":3.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reclassification of candidate splicing variants refines clinically conflicting interpretations in <i>SLC26A4</i>-associated hearing loss.","authors":"Yue Liang, Shubin Fang, Xiaoqing Cen, Yueying Wang, Anhai Chen, Lusha Huang, Juan Wang, Wenbin Lei, Guanxia Xiong, Kaitian Chen","doi":"10.1136/jmg-2024-110425","DOIUrl":"10.1136/jmg-2024-110425","url":null,"abstract":"<p><strong>Purpose: </strong>Variants in the human <i>SLC26A4</i> gene are a major cause of hereditary hearing loss. Many splice site variants have been identified, but their pathogenicity is not well understood.</p><p><strong>Methods: </strong>In accordance with the guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, we analysed the spectrum of <i>SLC26A4</i> gene variants. We performed in silico analysis and in vitro splicing assays to evaluate novel or known variants of uncertain significance that may contribute to aberrant alternative splicing.</p><p><strong>Results: </strong>In a cohort of 178 patients carrying <i>SLC26A4</i> variants, selected from 202 hearing loss patients with or without inner ear malformations who underwent <i>SLC26A4</i> gene testing, we identified a total of 50 variants. Among these, 10 intronic variants potentially affecting splicing collectively accounted for 54.8% of the total allele frequency of all identified variant types and were prioritised for messenger RNA (mRNA) splicing analysis. Further investigation demonstrated that four variants led to distinct types of aberrant splicing outcomes. Overall, the clinical significance of seven splice site variants was reclassified, representing at least 4.34% (14/323) of the variants within our cohort.</p><p><strong>Conclusion: </strong>By using the standard classification of <i>SLC26A4</i> variants, our results were able to interpret novel or uncertain <i>SLC26A4</i> gene variants in a pathogenic or benign variant direction. This approach facilitates more refined genetic counselling for patients carrying <i>SLC26A4</i> gene variants.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"516-522"},"PeriodicalIF":3.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}